Asthma is a chronic inflammatory airway disease currently affecting 1 in 12 adults in the United States. T helper (Th) cells are immune cells that orchestrate the lung inflammatory response in asthma through secretion of inflammatory cytokines and recruitment of other immune cells. While the Th2 subset of cells has been most commonly studied in asthma, Th17 cells have also been implicated in disease pathogenesis in at least some subtypes of asthma. Th17 cells mediate anti-bacterial and anti-fungal immunity and they are clearly associated with autoimmune diseases, but their precise role in the pathogenesis of asthma remains poorly understood. The proposed work aims to elucidate the regulation of Th17 cells by microRNAs (miRNAs) to gain a better appreciation of their dysregulation in diseases such as asthma. miRNAs have emerged as important regulators of many aspects of immune cell differentiation and function. The cell fate decisions of activated T helper cells are particularly sensitive to precise dosing of regulatory factors, and are therefore subject to regulation by the fine-tuning activity of miRNAs. Recent work has shown that the miR-17~92 cluster restrains the expression of subset-inappropriate genes in T follicular helper (TFH) cells. In contrast, how miR-17~92 regulates the differentiation and function of Th17 cells remains unknown. The major goal of this work is to define the role of the miR-17~92 cluster in Th17 cell differentiation in vitro and its potential functional significance in asthma using airway inflammation models. Aim 1 will combine the use of miR-17~92 conditional knockout mice and manipulation of individual miRNAs within the cluster to clarify the role of these miRNAs in regulating Th17 cell differentiation in vitro and by the examination of Th17 resident tissues in vivo. Preliminary data suggests that miR-17~92 inhibits Th17 cell differentiation, which is opposite to its effects in Th1, Th2, and TFH cells. Aim 2 will assess the mechanisms by which miR-17~92 cluster miRNAs target gene expression networks that control Th17 cell biology. Finally, Aim 3 will determine the impact of miRNA regulation of Th17 cells in asthma using airway inflammation models. This work will provide valuable insights into the molecular events that govern Th cell fate decisions and plasticity and its impact in a common chronic inflammatory disease. Additionally, this work may help identify more specific treatments and improve outcomes for patients with sub-phenotypes of asthma where Th17 cells play a significant role in the inflammatory response.